A Six-month Ketogenic Diet Alters The Immune And Metabolic Landscape In Multiple Sclerosis 2261201

Abstract Introduction A large body of preclinical research supports the immunomodulatory effects of diet, and dietary strategies for multiple sclerosis (MS) remain of major interest to clinicians and people with MS. Ketogenic diets produce anti-inflammatory effects in animal models of MS, but the effect in humans remains unknown. Methods Cryopreserved PBMCs and plasma were analyzed at baseline and after six months of MAD in 39 patients with relapsing MS who completed a previously-published phase 2 study of MAD. PBMCs were analyzed using single cell RNA sequencing, flow cytometry, and ex vivo stimulation assays. Plasma samples were subjected to metabolomics and multiplex ELISA. Results Six months of MAD produced substantial changes in the composition and transcriptional profiles of peripheral immune subsets associated with both innate and adaptive immunity. These changes included reduced pro-inflammatory phenotypes in myeloid cells, a shift from memory to naïve CD8 cells, increased abundance and suppressive activity of regulatory T (Treg) cells, and decreased B cell activation. Multiplex ELISA revealed that MAD significantly reduced plasma levels of pro-inflammatory cytokines and chemokines, such as IL-6 and CCL2. As a low carbohydrate/high fat diet, we hypothesized that MAD might shift the balance between glycolysis and fatty acid oxidation. As predicted, gene and protein expression patterns revealed metabolic reprogramming from glycolysis to fatty acid oxidation. These changes were corroborated by plasma metabolomics, which demonstrated a decrease in glycolytic products and an increase in fatty acid oxidation intermediates. Conclusion Our findings support the immunomodulatory potential of ketogenic diets in MS, demonstrating the capacity of MAD to reprogram immune cell metabolism and promote anti-inflammatory phenotypes. These results provide a rationale for larger, randomized studies comparing dietary interventions and evaluating clinical outcomes in MS. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)